Invasive fungal infections (IFIs) represent a growing challenge in modern medicine due to their increasing incidence, expanding spectrum of causative pathogens, and persistently high mortality, particularly among immunocompromised and critically ill populations. The pathobiology of these infections is complex and shaped by the dynamic interaction between fungal virulence factors, host immune responses, and environmental or iatrogenic factors that disrupt physiological barriers. Among the most relevant pathogens, Candida spp., Aspergillus spp., and Mucorales account for the majority of IFIs worldwide, although emerging molds and multidrug-resistant yeasts, such as Candidozyma auris/Candida auris, are gaining clinical importance. Their capacity to adhere to surfaces, form biofilms, evade host immunity, and invade tissues contributes to their clinical severity and therapeutic difficulty.
The pathogenesis of IFIs typically begins with host barrier disruption, either through epithelial damage, mechanical ventilation, indwelling devices, cytotoxic therapies, or underlying disease. Once inside the host, fungi deploy mechanisms such as hyphal invasion, angioinvasion, and secretion of tissue-destructive enzymes, enabling rapid dissemination. Invasive aspergillosis, for example, is characterized by hyphal penetration of pulmonary tissues, vascular invasion, thrombosis, and hemorrhagic necrosis. In contrast, invasive candidiasis is often driven by biofilm formation on intravascular devices, translocation from the gastrointestinal tract, and systemic immune dysregulation that precipitates multiorgan dysfunction.
Host immune pathways play a central role in shaping infection outcomes. Neutrophils, macrophages, and dendritic cells are essential for early fungal recognition and clearance, and defects in these compartments—through neutropenia, impaired phagocyte function, or corticosteroid therapy—dramatically increase susceptibility. Pattern-recognition receptors such as Dectin-1, toll-like receptor (TLR)2, and TLR4 detect fungal cell-wall components and trigger downstream inflammatory cascades. However, excessive or dysregulated immune activation can contribute to tissue damage, mirroring the dual-edged nature of host defense. Diagnosis of IFIs remains difficult due to nonspecific symptoms, low culture sensitivity, and delays in pathogen identification. Biomarkers such as galactomannan, β-D-glucan, and polymerase chain reaction (PCR)-based methods have improved early detection, but performance varies by patient population and fungal species. Imaging, particularly high-resolution computed tomography (CT), is essential for identifying characteristic patterns like nodular infiltrates, halo signs, or cavitation.
Management relies on early antifungal therapy, tailoring treatment based on pathogen type and host factors. Echinocandins, triazoles, and amphotericin B formulations remain the cornerstone of treatment, with therapeutic drug monitoring increasingly important for azole optimization. Despite advances, challenges persist related to antifungal resistance, diagnostic delays, and limited therapeutic options for emerging molds. Ongoing research in fungal genomics, immunotherapy, and host–pathogen interactions aim to advance precision diagnostics and improve outcomes in invasive fungal diseases.
Reference
Brown GD, Ballou ER, Bates S, et al. the pathobiology of human fungal infections. Nature Reviews Microbiolgoy. 2025.
